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NM_000162.5(GCK):c.562G>A (p.Ala188Thr) AND Maturity onset diabetes mellitus in young

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Nov 6, 2020
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV004017770.1

Allele description [Variation Report for NM_000162.5(GCK):c.562G>A (p.Ala188Thr)]

NM_000162.5(GCK):c.562G>A (p.Ala188Thr)

Gene:
GCK:glucokinase [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
7p13
Genomic location:
Preferred name:
NM_000162.5(GCK):c.562G>A (p.Ala188Thr)
HGVS:
  • NC_000007.14:g.44149986C>T
  • NG_008847.2:g.53185G>A
  • NM_000162.5:c.562G>AMANE SELECT
  • NM_001354800.1:c.562G>A
  • NM_033507.3:c.565G>A
  • NM_033508.3:c.559G>A
  • NP_000153.1:p.Ala188Thr
  • NP_001341729.1:p.Ala188Thr
  • NP_277042.1:p.Ala189Thr
  • NP_277043.1:p.Ala187Thr
  • LRG_1074t1:c.562G>A
  • LRG_1074t2:c.565G>A
  • LRG_1074:g.53185G>A
  • LRG_1074p1:p.Ala188Thr
  • LRG_1074p2:p.Ala189Thr
  • NC_000007.13:g.44189585C>T
  • NC_000007.13:g.44189585C>T
  • NM_000162.3:c.562G>A
Protein change:
A187T
Links:
dbSNP: rs751279776
NCBI 1000 Genomes Browser:
rs751279776
Molecular consequence:
  • NM_000162.5:c.562G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354800.1:c.562G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_033507.3:c.565G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_033508.3:c.559G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Maturity onset diabetes mellitus in young (MODY)
Synonyms:
Mason type diabetes
Identifiers:
MONDO: MONDO:0018911; MedGen: C0342276; Orphanet: 552; OMIM: 606391; Human Phenotype Ontology: HP:0004904

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV004848488Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
criteria provided, single submitter

(ACMG Guidelines, 2015)		Pathogenic
(Nov 6, 2020) 		germlineclinical testing

PubMed (13)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Spectrum of mutations in monogenic diabetes genes identified from high-throughput DNA sequencing of 6888 individuals.

Bansal V, Gassenhuber J, Phillips T, Oliveira G, Harbaugh R, Villarasa N, Topol EJ, Seufferlein T, Boehm BO.

BMC Med. 2017 Dec 6;15(1):213. doi: 10.1186/s12916-017-0977-3.

PubMed [citation]
PMID:
29207974
PMCID:
PMC5717832

Clinical application of ACMG-AMP guidelines in HNF1A and GCK variants in a cohort of MODY families.

Santana LS, Caetano LA, Costa-Riquetto AD, Quedas EPS, Nery M, Collett-Solberg P, Boguszewski MCS, Vendramini MF, Crisostomo LG, Floh FO, Zarabia ZI, Kohara SK, Guastapaglia L, Passone CGB, Sewaybricker LE, Jorge AAL, Teles MG.

Clin Genet. 2017 Oct;92(4):388-396. doi: 10.1111/cge.12988. Epub 2017 Apr 12.

PubMed [citation]
PMID:
28170077
See all PubMed Citations (13)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV004848488.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (13)

Description

The p.Ala187Thr (also known as p.Ala188Thr) variant in GCK has been reported in at least 11 individuals with maturity onset diabetes of the young (MODY) and segregated with disease in 7 affected individuals from at least 2 families (Bansal 2017 PMID: 29207974, Santan 2017 PMID: 28170077, Capuan 2012 PMID: 22761713, Feigerlova 2006 PMID: 16602010, Mantovani 2003 PMID: 12955723, Barrio 2002 PMID: 12050210, Pruhova 2010 PMID: 20337973, Shimada 1993 PMID: 8314448, Thomson 2003 PMID: 14517956). It has also been identified in 0.005438% (1/18390) of East Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has also been reported in ClinVar (Variation ID 804849). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In vitro functional studies provide some evidence that this variant impacts protein function (George 2014 PMID: 24578721, Takeda 1993 PMID: 8325892); however, these types of assays may not accurately represent biological function. Additional variants, resulting in different amino acid changes at the same position (e.g., p.A188G, p.A188P, p.A188V) have been reported in association with disease in the literature, supporting that a change at this position may not be tolerated. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant MODY. ACMG/AMP Criteria applied: PP1_Strong, PM2, PS4_Moderate, PP3, PS3_Supporting.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: May 7, 2024